JNJ-78911118 is a potent, blood-brain barrier-penetrating selective GluN2A antagonist (IC50= 44 nM). It demonstrates over 200-fold selectivity for GluN1/2B, 2C, and 2D receptors. As a negative allosteric modulator (NAM), JNJ-78911118 significantly reduces the potency of glutamate at GluN1/2A receptors and decreases the efficacy of glycine. It exhibits notable pharmacodynamic effects in vivo and is applicable in depression-related research.

GluN2A:44 nM

JNJ-78911118 (10 pM-10 μM, 2 hours) displaces binding at the GluN1/2A interface on hippocampal neuron membranes with the radioactive ligand JNJ-74950343 in a concentration-dependent manner, without affecting the efficacy of glutamate, but reducing its activity on homologous GluN1/2A receptors. JNJ-78911118 (10 μM, 24-72 hours) promotes neurite growth and synapse formation in rat hippocampal neuron cultures and significantly enhances various measures of dendritic complexity after 72 hours. JNJ-78911118 (1-10 μM) shows less than 50% inhibition across all targets in a custom screening panel of 77 ion channels, receptors, and transporters, as well as a panel containing 373 kinases.

JNJ-78911118, administered as a single subcutaneous dose of 60 mg/kg, can alleviate mechanical allodynia in a mouse model of inflammatory pain induced by Complete Freund's Adjuvant (CFA, HY-153808). It also inhibits hippocampal long-term potentiation and increases the frequency of miniature excitatory postsynaptic currents (mEPSC) in the rat prefrontal cortex. When given orally at doses of 50 and 250 mg/kg, twice daily for four consecutive days or twice in one day, JNJ-78911118 is generally well-tolerated in rats but does produce dose-dependent hemodynamic effects.